Method of manufacturing porous matrix-type controlled release systems using emulsion technique

ABSTRACT

A method of manufacturing a porous matrix-type drug delivery system is provided. It comprises the steps of: dispersing, stirring, and emulsifying an aqueous solution of a drug in an organic solvent having a polymer compound and a surface active agent solved therein; thereafter forming it into a desirable matrix shape; lyophilizing or drying it at a low temperature or room temperature until the matrix surface is hardened; and drying it again in order to remove the water and the organic solvent.

This application is a 371 of PCT/KR97/00289, filed on Dec. 31, 1997.

TECHNICAL FIELD

The present invention relates to a new method of preparing a matrix-typedrug delivery system that allows a controlled-release of drugs, andwhich has various porosity. The system is manufactured by evaporatingsolvents from the matrix that is-formed from an emulsion-solution. Theemulsion is made by emulsifying an aqueous solution containing awater-soluble drug in a polymer-dissolved organic solution using asurface-active agent.

BACKGROUND ART

Emulsion is a stable dispersion of one liquid in a second immiscibleliquid, and typically, a surface-active agent is used in order tomaintain the emulsion state.

The controlled-release is a characteristic that is capable of improvingeffects of medical usage, and of reducing its side-effects by making thedrugs to be released from the drug-containing substance according to atime schedule. Matrix system means that the drug is evenly or unevenlydissolved or dispersed inside a matrix, in which the matrix substance iscontinuously aligned.

The release of a water-soluble drug from a non-biodegradable matrix, orfrom a biodegradable matrix having a low degradation rate typicallyfollows first-order release kinetics, and its release rate decreasesgradually as time passes. [ Higuchi T., J. Pharm. Sci. 50, 874˜875(1961), Higuchi T., Pharm. Sci, 52, 1145˜1149 (1063), Manduit et al, J.controlled Release. 25, 43˜49 (1993)]. In general, the water-solubledrug cannot pass through the hydrophobic matrix. When a water-solubledrug is loaded in a hydrophobic polymer matrix below a percolationthreshold, only the drug exposed on its surface is released at aninitial period, while most of the drug still remains in the matrix evenafter a long time has passed. When the water-soluble drug is loadedabove the percolation threshold, its release rate depends on thesolubility of the drug in the body fluids, and on the diffusion of thedrug through the water channels generated by the drug dissolution afterthe drug is in contact with body fluids. Therefore, in the system loadedwith a low molecular compound having a high solubility, a large quantityof initial burst and fast release of the drug are shown. [Siegel et al,J. Controlled Release, 8,223˜236 (1989), Saltzman et al, J. Biophys.,55, 163˜171 (1989)].

In the case of a system in which a water-soluble drug of high osmoticactivity is dispersed inside the water-insoluble polymer matrix, thewater-soluble drug exposed on the surface is rapidly dissolved so as toform water-channels and is released at the initial period. The portionof the drug away from the water-channels functions as an osmoticpressure-causing material across the wall of the polymer matrix whichfunctions as pseudo-semipermeable membrane. The osmotic pressuregradually breaks the polymer matrix from an outermost to an inside, andthe drug is released in a controlled fashion. [Amsden et al,J.Controlled Release. 30, 45˜56 (1994), Amsden B G and Cheng Y., J.Controlled Release, 31,21˜32 (1994)]. Therefore, a drug that causes ahigh osmotic pressure can be released in a controlled-release fashion,and the remaining drug can be released even if in a case that the drugis loaded below the percolation threshold.

However, when the polymer matrix surrounding the drug is too thick, thepossibility of breaking the polymer matrix wall is very low, and therate of water passing through the polymer down to the drug is decreased,so that the release of the drug is very poor, and the more drug remainsin the matrix. [Zhang et al, J.Pharm, Pharmacol. 46, 718˜724 (1994),Amsden B G and Cheng Y., J. Controlled Release, 31, 21˜32 (1994)].

To load a water-soluble drug on a hydrophobic matrix, either simpledispersion of drug particles in an organic polymer solution, orextrusion or compression of the drug-polymer mixture in a solid phase isused. Those loading methods do not allow the even distribution of thedrug inside the matrix so that the rate change of the drug release isuneven as time passes.

DISCLOSURE OF THE INVENTION

A method of-manufacturing a porous matrix-type drug delivery systemaccording to the present invention comprises the steps of: dispersing,stirring, and emulsifying an aqueous solution containing a water-solubledrug in an organic solvent in which a polymer compound and a surfaceactive agent are dissolved therein; thereafter forming the resultantinto a desirable matrix shape lyophilizing or drying at a lowtemperature or at a room temperature until the matrix surface ishardened; and drying again to remove water and organic solvents.

The porous matrix-type controlled-release system of the presentinvention is a matrix substance for oral or non-oral administration ofdrugs, and can be widely and efficiently used as medical treatmentagents because the drugs can be released at a constant rate in adetermined period.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description given hereinbelow and the accompanying drawingswhich are given by way of illustration only, and thus are not limitativeof the present invention, and wherein:

FIG. 1 shows a SEM (Scanning Electron Microscope) image of across-sectional view of a poly-L-lactide film containing 20 wt % ofgentamycin according to a porous matrix-type controlled-release systemof the present invention before release;

FIG. 2 shows a SEM image of a sectional view of a poly-L-lactide filmcontaining 20 wt % of gentamycin according to porous matrix-typecontrolled-release system of the present invention after release;

FIG. 3 is a graph showing an early release vs. time relation of a porousmatrix-type controlled-release system according to the presentinvention;

FIG. 4 is a zero-order release graph of the long term release vs. timerelation of a porous matrix-type controlled-release system according tothe present invention;

FIG. 5 is a release graph of a porous matrix-type controlled-releasesystem of the present invention according to a change in theconcentration of span 80;

FIG. 6 shows a SEM image of a cross-sectional view of a poly-L-lactidefilm containing 10 wt % of cefotaxime sodium according to a porousmatrix-type controlled-release system of the present invention;

FIG. 7 is a drug release graph of polylactide-co-glycolide film andpoly-D,L-lactide film containing 20 wt % of gentamycin sulphateaccording to a porous matrix-type controlled-release system of thepresent invention; and

FIG. 8 shows a cross-sectional SEM view of a ethylene-vinylacetatecopolymer film containing 20 wt % of gentamycin sulphate according to aporous matrix-type controlled-release system of the present invention.

MODES FOR CARRYING OUT THE PREFERRED EMBODIMENTS

The present invention is directed to provide a method of dispersing awater-soluble drug evenly into a hydrophobic polymer matrix by anemulsion method by using an oil-soluble surface active agent. Thepresent invention is also directed to provide a method of manufacturingporous matrix-type controlled-release system containing an osmoticallyactive, water-soluble drug which is released by an induced osmoticpressure across a pseudo-semipermeable polymer matrix and/or a surfaceactive substance. The present invention has the following outstandingadvantages:

1. Constant release rate of drug;

2. Controllable release rate of drug; and,

3. Very low residual drug.

Due to a high porosity, most of the drug contained therein is releasedand a low osmotic pressure is needed to break the matrix wallsurrounding the drug.

To achieve the above objective and in accordance with the purposes ofthe present invention as embodied and described, a method ofmanufacturing a porous matrix-type drug delivery system is provided. Thesystem is constructed in such a manner that an aqueous solutioncontaining a water-soluble drug is dispersed and stirred to beemulsified in an organic solution that contains a polymer compound and asurface active agent. After forming it to a desired matrix shape, theemulsion is lyophilized immediately or dried at room temperatures (16 to30° C.) for a predetermined time (which can vary depending on theboiling point of the organic solution used) until the surface of thematrix is hardened. After the drying, vacuum-drying (below 0.75 mmHg) isperformed to remove organic solvents and water.

The polymer compounds which can be used as the matrix of the presentinvention are polylactide, lactide-glycolide copolymer, silicone rubber,ethylene-vinyl acetate copolymer, polyortho-ester copolymer, etc.Especially polylactide, lactide-glycolide polymer is suitable because itis widely used as biocompatible and biodegradable materials, as in thecase of raw materials for suture materials. The polylactide used in thisinvention is a homopolymer having an average molecular weight of 100,000(Polyscience. Inc of U.S., example 1,2,3), and the lactide-glycolidecopolymer is Resomer RG858 (Boehringer Ingelheim of Germany, example 4).Ethylene-vinylacetate copolymer (Aldrich Chemical Company, Inc. of U.S.its vinyl-acetate is 33%, example 5), which does not decompose but itsbiocompatibility is excellent, is used.

The surface-active agent of the present invention can be selected from agroup consisting of fat-acid, olefin, alkylcarbonyl, silicon elastomer,sulfate ester, petty alcohol sulfate, sulfate pete and oil, sulfonicacid-base, fat sulfonate, alkylaryl sulfonate, ligmin sulfonate,phosphoric acid ester, polyoxyethylene, polyoxyethylene caster oil,polyglycerol, polyol, imidazol, altanolamine, hetamine, sulfobecamine,phosphotide, polyoxyethylene-sorbitan fat acid ester (Tween), sorbitanester (Span), etc. and preferably, sorbitan monooleate (Span 80) of asorbitan ester. Its concentration is preferable to be 0.1 to 5 wt % forthe emulsion solution. The release rate of the drug, that is, drugrelease amount per time is changed depending on the kind and density ofthe surface active agent (example 2). The usage of the surface activeagent is limited to above, wherein the emulsion is difficult to achievebelow those density, and above those density, the release rate is tooslow, and side-effects may occur in clinical applications.

A variety of drugs can be used in the present invention. These includeanalgesics, anti-inflammatory agents, vermicide, cardiovascular drugs,urological drugs, antibiotic agents, anticoagulating agents,antidepressant, diabetes treatment agents, antiepileptic agents,antihypertensive agents, antifebrile, hormones, antiasthmatic agents,bronchodilators, diuretics, digestive agents, sedatives, hypnotics,anesthetics, nutritional and tonic agents, antiseptic agents,preservation agents, stabilization agents, insecticide, disinfectant,muscle-relaxant, antituberculosis and antileprosy agents, vaccines, etc.Although it depends on the therapeutic concentration of the drug,water-soluble drugs where the solubility of which is over 1 mg/ml ispreferable. When the solubility is low, the maximum drug loadingachievable by the present invention is too small.

As the organic solvents of the present invention, butyl alcohol,chloroform, cyclohexan, dichlorometan, dichloroethan, ethylacetate,ethylether, dipropylether, toluene, etc. can be used.

The volume ratio of the aqueous solution and the organic solvent ispreferable to be 1:2˜1:40. The initial burst of the drug can beincreased by increasing the volume ratio of the aqueous solution. Thereason why the range of the volume ratio is set is that the high volumeratio of the solutions makes the emulsion formation difficult, and evenwhen the emulsion is formed, the initial release amount of drug is toohigh. The shape of the matrix can be manufactured variously depending onthe purpose, such as film, surface coating, pellet, tablet, plate, rod,etc.

The emulsification can be achieved by using well-known tools such asstirrer, vortex mixer, homogenizer, ultrasonic device, microfluidizer,etc.

Reference will now be made in detail to the preferred embodiments of thepresent invention, but the substitutions and alterations can be madehereto without departing from the spirit and scope of the invention asdefined by the claims.

EXAMPLE 1

A 50% aqueous gentamycin solution was poured into a polymer solution ofdichloromethan having 16% of poly-L-lactide (weight averaged molecularweight of 100,000), and 3% of span 80 (wt %). The weight of gentamycinwas 20% of the weight of poly-L-lactide. The mixture solution was evenlyemulsified by using a vortex mixer, a stirrer and a sonicator. Theemulsion was cast on a clean glass plate and the thickness was adjustedby using an applicator of 1 mm height. It was dried at room temperaturesfor 4 hrs. and then vacuum-dried for 24 hrs. to form a solid film. SEMpictures of the film were taken before and after the release of thedrug. The porosity of the film was determined by the amount of waterincluded in the emulsion. (FIG. 1 and 2).

Drug Release Embodiment

Except for the change of gentamycin concentration of the aqueoussolution in example 1 to 25%, 35%, 50%, the films were manufactured inthe same manner as example 1. The films were cut into same sizes, andthe release rate was measured by immersing the films in PBS of pH 7.4.

Comparative Example 1 Initial Release

The initial release of drug was increased with the increase of the wateramount in the emulsion. (FIG. 3)

Comparative Example 2 O-Order Release for Long Term

After the period of initial release, zero-order release is maintainedfor a long-time. (FIG. 4)

EXAMPLE 2

Except for the change of gentamycin concentration of the aqueoussolution in example 1 into 35%, and the change of span 80 concentrationinto 0.5%, 1%, 1.5%, 3%, the films were manufactured in the same way asexample 1. The films were cut into same sizes and the drug was releasedin PBS of pH 7.4. The initial burst and release rate of the drugs werechanged depending on the concentration of the span 80. (FIG. 5)

EXAMPLE 3

A 10% aqueous cefotaxime sodium solution was poured into a polymersolution of methylene chloride having 16 wt % of poly-L-lactide (averagemolecular weight of 100,000), and 1 wt % of span 80. The weight of thecefotaxime sodium was 20 wt % of the weight of lactide-glycolidecopolymer. The mixture solution was evenly emulsified by using a vortexmixer, a stirrer and a sonicator. The emulsion was cast on a clean glassplate and the thickness was adjusted by using an applicator of 1 mmheight. It was dried at room temperatures for 4 hrs. and then wasvacuum-dried for 24 hrs. to form a solid film. SEM pictures of the filmwere taken before and after the release of the drug. The porosity of thefilm was determined by the amount of water included in the emulsion.(FIG. 6)

EXAMPLE 4

A 35 wt % aqueous gentamycin sulfate solution was put into a polymersolution of chloroform having 16 wt % of lactide-glycolide copolymer(Resomer RG858, Boehringer Ingelheim, Germany) and 1 wt % of span 80 orinto a polymer solution of chloroform having 16 wt % of poly-D,L-lactid(Resomer R207, Boehringer Ingelheim, Germany), and 1 wt % of span 80.The weight of gentamycin sulfate was 20% of the weight of polymers. Themixture solution was evenly emulsified by using a vortex mixer, astirrer and a sonicator. The emulsion was cast on a clean glass plateand the thickness was adjusted by using an applicator of 1 mm height. Itwas dried at room temperatures for 4 hrs. and then was vacuum-dried for24 hrs. to form a solid film. The films were cut into same sizes and thedrug was released in PBS of pH 7.4. The drug was also released in acontrolled fashion even when using the lactide-glycolide copolymer orpoly-D,L-lactide. Especially, the release rate of poly-D,L-lactide filmwas faster than that of poly-L-lactide film. (FIG. 7)

EXAMPLE 5

A 35 wt % aqueous gentamycin sulfate solution was put into a polymersolution of chloroform having 20 wt % of ethylene-vinylacetate copolymer(weight averaged molecular amount 130,000, ethylene:vinylacetate=67:33), and 1 wt % of span 80. The weight of gentamycinsulfate was 20% of the weight of ethylene vinylacetate copolymer, Themixture solution was evenly emulsified by using a vortex mixer, astirrer and a sonicator. The emulsion was cast on a clean glass plateand the thickness was adjusted by using an applicator of 1 mm height. Itwas dried at room temperatures for 4 hrs. and then vacuum-dried for 24hrs. to form a solid film. SEM pictures of the film were taken beforeand after the release of the drug. The porosity of the film wasdetermined by the amount of water included in the emulsion. (FIG. 8)

What is claimed is:
 1. A method of manufacturing a porous matrixcontrolled release drug delivery substance wherein the drug is presentin the pores of the matrix comprising the steps of: dispersing,stirring, and emulsifying an aqueous solution containing a water solubledrug in an organic solvent in which a polymer compound and a surfaceactive agent are dissolved in a water-in-oil type emulsion, wherein saidsurface active-agent is present in the amount of about 0.1 to about 5%wt of the emulsion; thereafter forming the emulsion into a desirablematrix shape; drying at room temperature until the matrix surface ishardened; and vacuum drying to remove water and the organic solvent. 2.The method as claimed in claim 1, wherein the polymer compound isselected from the group comprising of poly(l-lactide), poly(dl-lactide),polyglycolide, lactide-glycolide copolymers, poly ortho-estercopolymers, ethylene-vinyl acetate copolymers, and ethylene-vinylalcohol copolymers.
 3. The method as claimed in claim 1, wherein thesurface-active agent is selected from the group consisting of sorbitanesters and polyoxyethylene sorbitans.
 4. The method as claimed in claim1, wherein the drug is a water-soluble drug for oral and non-oraladministration that is dissolved in an inner aqueous solution inside thewater-in-oil type emulsion.
 5. The method as claimed in claim 1, whereinthe organic solvent is selected from the group comprising ofdichloromethane and chloroform.
 6. The method as claimed in claim 1,wherein the volume ratio of the aqueous solution to the organic solventis 1:2˜1:40.